The field of the present invention is immunology, especially the area of vaccines, and in particular to compositions and methods for generating immune response to sialic acid-containing immunogenic compositions, which further contain a sialic acid binding component such as an orthomyxovirus or a paramyxovirus or an orthomyxovirus.
T cell-independent (TI) antigens are antigens that stimulate antibody responses in the absence of MHC class II-restricted T cell help. TI antigens fall into two major categories, TI type 1 (TI-1) and TI type 2 (TI-2). TI-1 antigens are characterized by being mitogenic and inducing polyclonal B cell proliferation. TI-2 antigens, which are represented by polysaccharides, have the properties of a high molecular weight, repeating antigenic epitopes, and inability to stimulate MHC class II-dependent T cell help (Mond et al. (1995a) Annu. Rev. Immunol. 13:655; Mond et al. (1995b) Curr. Opin. Immunol. 7:349; and Mosier et al. (1977) J. Immunol. 119:1874.) TI antigens induce only IgM responses. In contrast, protein antigens are thought to induce only T cell-dependent antibody responses, which include both IgM and IgG responses (Mond et al. (1995a) supra; Mond et al. (1995b) supra).
Two kinds of viral vaccines are currently being widely used: live attenuated viruses and formalin inactivated viruses. Live attenuated vaccines usually lead to excellent, often life-long, immunity to the vaccinated pathogen (Sabin et al. (1985) J. Infect. Dis. 151:420; and Salk, J., and Salk D. (1977) Science 195:834). However, in some instances, live attenuated viral vaccines can regain their virulence and cause serious complications (Evans et al. (1985) Nature 314:548; and Nkowane et al. (1987) Jama 257:1335). Inactivated vaccines are the only currently available vaccines for some diseases, including influenza. Disadvantages of the inactivated vaccines are that they induce lower titers of antibody, restricted isotype pattern, shorter duration of immunity and lack of cell-mediated immunity. (Horstmann, D. M. (1979) Rev. Infect. Dis. 1:502; and Horstmann, D. M. (1982) J. Infect. Dis. 146:540).
CD4 T helper cells are believed to be essential for induction of a high-affinity antibody response and for efficient isotype switching from IgM to IgG production (Oxenius et al. (1998) Adv. Immunol. 70:313; and Parker, D. C. (1993) Annu. Rev. Immunol. 11:331).
Through cognate interaction between antigen specific B cell and CD4 αβ T cells, the CD4+ αβ T cells secrete cytokines that initiate the immunoglobulin class switching process from IgM to IgG (Parker, D. C. (1993) Annu. Rev. Immunol. 11:331; Finkelman et al. (1990) Annu. Rev. Immunol. 8:303; and Snapper, C. M. and Mond, J. J. (1993) Immunol. Today 14:15). These T cell dependent antibody responses are accompanied by the formation of germinal centers of B cells in the lymphoid organs such as the spleen and lymph nodes. Recent studies have shown that Ig class switching can also be induced in T cell deficient mice when infected with live viruses (Maloy et al. (1998) Proc. Natl. Acad. Sci. USA 95:1160; Szomolanyi-Tsuda, E. and Welsh, R. M. (1996) J. Exp. Med. 183:403; and Szomolanyi-Tsuda et at. (1998) J. Virol. 72:6665). When T cell deficient mice (T cell receptor β chain knockout [TCRβ−/−] or T cell receptor α chain knockout [TCRα−/−] were infected with live polyoma viruses, a protective, virus-specific IgG response was reported in the absence of helper T cells. However, virus-like particles and soluble capsid antigens (VP1) were reported not to induce detectable IgG responses. In studies with VSV, TCRα−/− mice were found to produce neutralizing IgG antibodies when infected with live VSV or with a recombinant vaccinia virus expressing the VSV glycoprotein (Maloy et al. (1998) supra). These results suggest that there may be alternative mechanisms for antibody class switching and induction of IgG responses.
Formalin inactivation of VSV was reported to have no effect on the early IgM response after immunization, but class switching from IgM to IgG was significantly reduced (Freer et al. (1994) J. Virol. 68:3650; Bachmann et al. (1993) J. Virol 67:3917; and Bachmann et al. (1995) Eur. J. Immunol. 25:3445). Low doses (2×104 PFU) of inactivated VSV virus did not induce any measurable neutralizing IgG responses, while high IgG titers were produced after immunization with the same dose of live viruses. Higher dose (2×106 PFU and 1×108 PFU) of inactivated VSV viruses induced almost normal level of neutralizing IgG titers. However, when nude mice or mice depleted of CD4+ T cells by anti-CD4 monoclonal antibody were immunized with inactivated virus, no detectable virus-specific IgG was produced (Bachmann et al. (1993) J. Virol. 67:3917). It was therefore concluded that CD4+ T cells were strictly required for the generation of class switching from IgM to IgG when inactivated virus vaccines are used.
There is a need in the art for effective methods for immunization of immune compromised humans and animals, particularly those humans and animals who are deficient in CD4+ T cells, and for improved methods for immunization of humans and animals in general. The present invention fulfills this need.